TDP43 pathology in primary progressive aphasia and frontotemporal dementia with pathologic Alzheimer...

TDP-43 pathology in primary progressive aphasia andfrontotemporal dementia with pathologic Alzheimer disease

Eileen H. Bigio,Cognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School ofMedicine, Chicago, IL 60611, USA. Department of Pathology, Northwestern University FeinbergSchool of Medicine, 710 N. Fairbanks Ct., Olson 2-459, Chicago, IL 60611, USA

Manjari Mishra,Cognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School ofMedicine, Chicago, IL 60611, USA

Kimmo J. Hatanpaa,Department of Pathology, Alzheimer Disease Center, University of Texas Southwestern MedicalCenter, Dallas, TX 75390, USA

Charles L. White III,Department of Pathology, Alzheimer Disease Center, University of Texas Southwestern MedicalCenter, Dallas, TX 75390, USA

Nancy Johnson,Cognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School ofMedicine, Chicago, IL 60611, USA. Department of Neurology, Northwestern University FeinbergSchool of Medicine, Chicago, IL 60611, USA

Alfred Rademaker,Cognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School ofMedicine, Chicago, IL 60611, USA. Department of Preventive Medicine, Northwestern UniversityFeinberg School of Medicine, Chicago, IL 60611, USA

Bing Bing Weitner,Department of Preventive Medicine, Northwestern University Feinberg School of Medicine,Chicago, IL 60611, USA

Han-Xiang Deng,Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611,USA

Steven D. Dubner,Cognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School ofMedicine, Chicago, IL 60611, USA. Department of Pathology, Northwestern University FeinbergSchool of Medicine, 710 N. Fairbanks Ct., Olson 2-459, Chicago, IL 60611, USA

Sandra Weintraub, andCognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School ofMedicine, Chicago, IL 60611, USA. Department of Psychiatry, Northwestern University FeinbergSchool of Medicine, Chicago, IL 60611, USA

Marsel Mesulam

Correspondence to: Eileen H. Bigio, [email protected].

NIH Public AccessAuthor ManuscriptActa Neuropathol. Author manuscript; available in PMC 2010 July 14.

Published in final edited form as:Acta Neuropathol. 2010 July ; 120(1): 43–54. doi:10.1007/s00401-010-0681-2.

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Cognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School ofMedicine, Chicago, IL 60611, USA. Department of Neurology, Northwestern University FeinbergSchool of Medicine, Chicago, IL 60611, USAEileen H. Bigio: [email protected]

AbstractThe clinical syndrome of primary progressive aphasia (PPA) can be associated with a variety ofneuropathologic diagnoses at autopsy. Thirty percent of cases have Alzheimer disease (AD)pathology, most often in the usual distribution, which defies principles of brain–behaviororganization, in that aphasia is not symptomatic of limbic disease. The present study investigatedwhether concomitant TDP-43 pathology could resolve the lack of clinicoanatomic concordance. Inthis paper, 16 cases of clinical PPA and 10 cases of primarily non-aphasic frontotemporal dementia(FTD), all with AD pathology, were investigated to determine whether their atypical clinicalphenotypes reflected the presence of additional TDP-43 pathology. A comparison group consistedof 27 cases of pathologic AD with the typical amnestic clinical phenotype of probable AD.Concomitant TDP-43 pathology was discovered in only three of the FTD and PPA but in more thanhalf of the typical amnestic clinical phenotypes. Hippocampal sclerosis (HS) was closely associatedwith TDP-43 pathology when all groups were combined for analysis. Therefore, the clinicalphenotypes of PPA and FTD in cases with pathologic AD are only rarely associated with TDP-43proteinopathy. Furthermore, medial temporal TDP-43 pathology is more tightly linked to HS thanto clinical phenotype. These findings challenge the current notions about clinicopathologiccorrelation, especially about the role of multiple pathologies.

KeywordsPrimary progressive aphasia; Frontotemporal dementia; Alzheimer disease; FTLD-TDP; TDP-43proteinopathy; Hippocampal sclerosis

IntroductionBrain autopsies from patients presenting clinically with primary progressive aphasia (PPA),as well as behavioral and mixed variants of frontotemporal dementia (FTD), most oftendemonstrate frontotemporal lobar degeneration with either tau positive (FTLD-tau), TDP-43positive (FTLD-TDP), or FUS positive (FTLD-FUS) inclusions [24,34]. There may remainrare cases with no immunohistochemically demonstrable inclusions (dementia lackingdistinctive histopathology or DLDH), but most of these have been found to have inclusionswhen sensitive immunostaining protocols are used [19,22,25]. However, as has recently beenshown, many cases of PPA and FTD may have Alzheimer disease (AD) pathology at autopsy,including the typical concentration of neurofibrillary tangles within memory-related parts ofthe medial temporal lobes [28]. How can such a neuropathologic pattern lead to apredominantly behavioral or aphasic rather than amnestic clinical phenotype? One mightsurmise that these cases represent an anatomically atypical form of AD or that they haveconcurrent neuropathologic processes masked by the AD. Previous work on a small numberof cases showed that the anatomic distribution and the density of Alzheimer pathology in casespresenting clinically with PPA is not consistently different from cases presenting with dementiaof the Alzheimer-type (DAT) [28]. Although these patients had a progressive aphasia that wasinitially unaccompanied by memory loss, the neurofibrillary tangle (NFT) counts were stillmany times higher in the hippocampo-entorhinal complex than in language cortices, and mostof the patients showed no asymmetry of neocortical NFT even though they had phenotypicallyconcordant symmetric atrophy of the left hemisphere. Another possibility that could resolvethis apparent lack of clinico-anatomic concordance is the possibility of other pathologic

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processes. A limited survey in 11 cases did not reveal additional TDP-43 pathology in a groupof 11 PPA-AD cases [28]. The current study represents an expansion of this investigation toinclude additional brain regions in a larger set of 53 cases.

Pathologic overlap of AD and tau-negative FTLD could not be ascertained prior to theidentification of TAR DNA-binding protein of 43 kDa mw (TDP-43) as the major proteincomponent in the ubiquitinated inclusions in the majority of cases of FTLD-U, now known asFTLD-TDP [3,7,9,36]. TAR DNA-binding protein (TDP-43) is normally located in thenucleus, and is functionally implicated in exon skipping and transcription regulation [3,7,9,36]. In most FTLD-U cases, neuronal cytoplasmic inclusions (NCIs), neuronal intranuclearinclusions (NIIs), and dystrophic neurites (DNs) are composed primarily of TDP-43, andnormal nuclear TDP-43 is lost in neurons containing NCIs or NIIs. In most autopsy brains withAD pathology, tangles and plaques are so dense and widespread that they can mask tau- andubiquitin-positive deposits characteristic of FTLD sub-types, so prior to the discovery ofTDP-43, it was virtually impossible to identify pathologic overlap of AD and FTLD. Unlessubiquitin-positive neuronal intranuclear inclusions (NIIs) were identified in cases withpathologic AD, the diagnosis of concomitant FTLD-U could not be made with confidence. Itremains difficult to diagnose concomitant FTLD-Tau, but TDP-43 IHC now provides a toolto immunohistochemically investigate the potential overlap of AD and FTLD-U/TDP, the mostcommon FTLD sub-type [19,22].

TDP-43-positive inclusions have been demonstrated in association with various otherneurodegenerative disorders, including AD[1,4,17,18,21,39,41], hippocampal sclerosis (HS)[1,41], dementia with Lewy bodies (DLB) [4,17,32], corticobasal degeneration (CBD) [41],Pick disease [3,12], ALS–parkinson–dementia complex of Guam (ALS-PDC Guam) [14,15,29], argyrophilic grain disease (AGD) [13], Huntington disease (HD) [40], Perry syndrome[11,44], and protein aggregate myopathies [37,42]. They are also characteristic of sporadicamyotrophic lateral sclerosis (ALS) and familial ALS without SOD1 mutations [3,23,36]. InAD and HS, TDP-43 pathology is most often localized to the medial temporal regions—including the hippocampal dentate gyrus, entorhinal cortex, and amygdala (FTLD-TDP, limbictype), sometimes including involvement of superficial layers of the inferior temporal cortex.A minority of cases appear to have more widespread cortical involvement, so characteristic ofFTLD-TDP, called FTLD-TDP, diffuse type by Amador-Ortiz et al. [1].

Because TDP-43 pathology may be present in up to 30% of AD cases [1,4,17,18,21,39,41],we reasoned that there might be an even greater proportion of cases with concomitant TDP-43pathology in PPA and FTD syndromes with AD pathology in a way that may explain the clinicalphenotype. In a previous study, TDP-43 immunostains of hippocampus, including dentategyrus and entorhinal cortex, and frontal cortex were negative in 11 cases of PPA with ADpathology [28]. The current study looked in greater detail at the same 11, five additional casesof PPA, and 10 cases of FTD with AD pathology in order to determine whether concomitantFTLD-TDP pathology might be responsible for the clinical phenotypes. Additional regionsincluded amygdala since TDP-43 pathology can be confined to this region, and inferior andsuperior temporal gyri. TDP-43 IHC was performed using three different immunostainingprotocols on sections from the same anatomic regions and also on amygdala and inferior andsuperior temporal cortex from these 26 cases. After performing TDP-43immunohistochemistry (IHC) on the PPA-AD and FTD-AD groups three times using differentprotocols and finding only a small percentage of cases with TDP-43 pathology, much less isreported in the literature for AD [1,4,17,18,21,39,41], we decided to perform TDP-43 IHC ona group of 27 cases of pathologic AD presenting with amnestic dementia (clinical diagnosisof DAT) for comparison.

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Materials and methodsPPA and FTD groups

Of 60 Northwestern PPA and FTD brain autopsies (28 PPA, 32 FTD), 26 had the pathologyof AD and 34 did not have pathologic AD; of these 34, 32 had FTLD without AD (21 FTLD-TDP, 9 FTLD-tau, and 2 FTLD-FUS), and two others had vascular dementia and non-specificmorphologic changes. Average ages of onset and of death and average duration of disease weregreater in the group with pathologic AD, reaching statistical significance in age of death (p =0.005) and duration (p = 0.004) (see Table 1). The focus of this study was those cases of PPA(n = 16) and FTD (n = 10) with the pathology of AD. The cases with non-AD pathologicdiagnoses are not part of the current study.

DAT groupTDP-43 pathology in the PPA and FTD cases was compared to TDP-43 pathology in 27 casesof AD presenting clinically with DAT, for a total of 53 cases. Cases with concomitant Lewybody dementia (DLB) pathology were excluded from this group to avoid multiple variables.

Clinical informationDetailed clinical data were available from 14 of the 16 PPA and all of the 10 FTD patients withAD pathology. The diagnosis of primary progressive aphasia (PPA) was based on theperformance on neuropsychological tests, a comprehensive clinical evaluation, and the criteriaoutlined by Mesulam [27]. The diagnosis of behavioral variant FTD (bvFTD) was made by aneurologist, performing a comprehensive clinical evaluation and neuropsychological testing,utilizing criteria outlined by the most recent work-group consensus on frontotemporal lobardegeneration [33]. The presence of changes in social–interpersonal behaviors, personality, andcustomary ways of behaving were paramount in this diagnostic category. The other FTDsubjects had a variety of clinical deficits associated with frontotemporal function, includingexecutive and attentional dysfunction in the absence of comportmental symptoms, or a mixtureof behavioral and aphasic disturbances. Detailed clinical information was available from all ofthe 27 amnestic dementia patients. The diagnosis of probable AD was made according tocurrently accepted criteria [26].

Table 2 shows the clinical, pathologic, and genetic information in the study groups withpathologic AD. The average age of onset was significantly younger in the PPA-AD (p = 0.03)and FTD-AD (p = 0.0008) groups than in the probable AD/DAT-AD group. The average ageof death in the PPA-AD group was younger than the DAT-AD group (p = 0.014) and olderthan the FTD-AD group (p = 0.048). The average age of death in the FTD-AD group was alsoyounger than the DAT-AD group (p = 0.0003). Duration was shorter in the FTD-AD groupthan in the PPA-AD and DAT-AD groups, but the difference was not statistically significant.There was a higher male:female ratio in the PPA-AD and FTD-AD groups, while the oppositewas true in the DAT-AD group, but the differences were not significant. The average brainweight in the FTD-AD group was significantly heavier than both the PPA-AD (p = 0.003) andDAT-AD (p = 0.007) groups, which may be related to the shorter duration for this group. TheApoE ε4 allele was present in 79% of the DAT-AD subjects, significantly higher than itspresence in 36% of the PPA-AD subjects (p = 0.047) but similar to the FTD-AD group (78%)(p = 0.999). PROGRANULIN (PGRN) mutation analysis was performed on 10 of the 16 PPAand 7 of the 10 FTD cases, and no mutations were identified [5,8]. This analysis included twoof the three cases with TDP-43 pathology, one with NIIs and one without NIIs.

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Neuropathologic evaluationAutopsies were performed by the Neuropathology Core of the Northwestern CNADC. Allbrains were evaluated grossly for cortical, caudate, hippocampal, cerebellar, and brainstematrophy, and microscopically with H&E for neuronal loss, astrocytosis, superficialmicrovacuolation, and depopulation of pigmented nuclei. All brains were evaluated for ADpathology using thioflavine-S, Gallyas, tau IHC (AT8, Pierce-Endogen, Rockford, IL, USA),and A beta IHC (4G8, Signet, Dedham, MA, USA), for Lewy body pathology with α-synuclein(LB509, Zymed-Invitrogen, Carlsbad, CA, USA), and for non-Alzheimer- and non-Lewy-typedeposits of tau, α-synuclein, and ubiquitin (DAKO polyclonal, Carpinteria, CA, USA).

All of the cases with pathologic AD, regardless of the clinical diagnosis, had CERAD C, BraakV or VI, and NIA/Reagan high likelihood dementia due to AD [2,6,30]. Because we did notwish to exclude any of the PPA or FTD cases with AD pathology from this study, we did notexclude cases that had concomitant DLB. Two of the PPA cases also had DLB: one had DLBbrainstem stage and one had DLB cortical stage or DLBD. One FTD case also had DLB limbicstage.

Ubiquitin immunohistochemistryBriefly, 3-um sections from all cases were pre-treated with formic acid for 5 min andmicrowaved in 10 mM Citrate buffer pH 6.0 for 10 min, incubated with polyclonal ubiquitinantibody (Cat # Z0458, DAKO, Denmark), biotinylated secondary antibody, and VectastainElite ABC reagent (Vector Laboratories, Cat #PK 6100, Burlingame, CA, USA). EnhancedDAB metal substrate chromagen was used for visualization (Cat # 34065, Pierce-Endogen,Rockford, IL, USA). Slides were counterstained with hematoxylin for 30 s.

TDP-43 immunohistochemistryFrontal (middle frontal gyrus, BA8–9) and temporal (superior temporal gyrus, BABA41–42)cortex, hippocampus with dentate gyrus, subiculum and parahippocampal gyrus, entorhinalcortex, and amygdala with inferior temporal gyrus (BA20) from all cases were immunostainedwith a polyclonal antibody to TDP-43 (Proteintech Group, Chicago, IL, USA). Four-micronsections were deparaffinized, pretreated in an antigen decloaking chamber at 100 °C with 10mM citrate buffer, pH 6.0, for 20 min to enhance immunoreactivity, quenched for endogenousperoxidase, blocked for non-specific activity in 2% non-fat dried milk, and incubated with anti-TDP-43 antibody (1:1,000) overnight at 4°C. Sections were incubated with biotinylated goatanti-rabbit IgG secondary antibody (Biocare Medical, Concord, CA, USA) for 30 min followedby peroxidase-conjugated streptavidin in PBS with carrier protein (BioGenex, San Ramon,CA, USA) for 20 min and developed with AEC chromagen (Biogenex) for 5 min.Counterstaining was carried out with hematoxylin for 45 s and slides mounted with Advantagepermanent aqueous mounting media (Innovex Biosciences).

Because we did not see TDP-43 immunopositivity in 25–30% of our PPA or FTD cases withAD pathology, as had been published at that time [1], two additional TDP-43immunohistochemical methods were used for the PPA or FTD with AD pathology cases, asoutlined below. Following discussions with collaborators who used alternative protocols,TDP-43 IHC was repeated using a modified protocol. Sections were deparaffinized andquenched for endogenous peroxidase for 30 min in 300 ml of methanol containing 4 ml ofcommercially available stock 30% hydrogen peroxide. Antigen retrieval was performed withvector antigen unmasking solution (Vector laboratories, cat# H-330). Anti-TDP-43 antibody(Polyclonal, Proteintech, Chicago, IL, USA) at 1:8,000 in 0.1 M Tris/2% FBS was appliedovernight at 4°C. The signal was developed using Biogenex Super Sensitive Polymer Detectionkit (Biogenex QD430-XAK). Briefly, Super Enhancer was applied for 20 min at room

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temperature, followed by poly-HRP for 30 min and DAB chromagen (Biogenex, HK542-XAK)for 5 min, and counterstained with hematoxylin.

In addition, TDP-43 IHC was performed again at UT Southwestern on hippocampus/entorhinalcortex sections, following a previously published, enhanced, highly sensitive TDP-43 IHCprotocol [16]. Briefly, for antigen retrieval, the sections were placed in a Pascal programmablepressure cooker (DakoCytomation, Carpinteria, CA, USA) containing Reveal solution(Biocare Medical, Concord, CA, USA), with the target temperature and time set to 126°C for30 s. After the temperature dropped to 89°C, the slides were taken out and allowed to cooldown at room temperature for 10 min. The primary antibody was a rabbit polyclonal antibodyto TDP-43 at a dilution of 1:1,000 (ProteinTech, Chicago, IL, USA). The detection system wasthe alkaline phosphatase-based ultra View Red detection system (Ventana Medical Systems,Tucson, AZ, USA); the chromagen was Fast Red/Naphthol, and the procedure was performedusing the Benchmark XT automated stainer (Ventana).

TDP-43 pathologyTDP-43-labeled NCIs, NIIs, and DNs were estimated semiquantitatively; TDP-43 labeling oftangles and Lewy body pathology was noted but not included in this analysis. TDP-43-labeledneuronal cytoplasmic inclusions (NCIs), neuronal intranuclear inclusions (NIIs), anddystrophic neurites (DNs) in each region were semi-quantitatively estimated in threemaximally labeled 200× fields and averaged. These were designated as “rare” (generallyequivalent to <1 inclusion per 200× field), “sparse” (equivalent to 1–3 inclusions per 200×field), “moderate” (equivalent to 4–8 inclusions per 200× field), or “frequent” (equivalent to>9 inclusions per 200× field). For statistical analysis, these ratings were given numbers: rare0.5, sparse 1, moderate 2, and frequent 3. Finally, for each case, the averages for all regionswere added. The group score was then derived by dividing the added total scores by the numberof cases in that group. This method of scoring allowed statistical comparisons between groups.

Confocal microscopyConfocal microscopy was performed using previously described methods [10]. In brief, 6-μmsections were cut from formalin-fixed, paraffin-embedded tissues. Antigen retrieval wascarried out using a decloaking chamber (Biocare Medical, Walnut Creek, CA, USA).Antibodies to TDP-43 and α-synuclein or TDP-43 and Tau (AT8) were used in combinationas primary antibodies. Fluorescence signals were detected with donkey anti-rabbit IgGconjugated with FITC (Thermo Scientific, Rockford, IL, USA) and goat anti-mouse IgGconjugated with rhodamine (R-6393, Invitrogen, Carlsbad, CA, USA) using an LSM 510META Laser Scanning Confocal Microscope with the multitracking setting. The same pinholediameter was used to acquire each channel.

Hippocampal sclerosisFor both the hippocampal CA1 region and the subiculum, each case was semi-quantitativelyestimated for neuronal loss and gliosis, from absent to severe, on a 0–3 point scale (0 notpresent; 1 mild; 2 moderate; 3 severe). Hippocampal sclerosis (HS) was defined as severeneuronal loss and gliosis in both regions.

Statistical analysisDiagnostic groups were compared using one-way analysis of variance followed by post-hocpairwise t tests for age, duration, and brain weight. Frequencies of gender and ApoE statuswere compared across groups using Fisher’s exact test, which was also used for the post-hocpairwise comparisons. The occurrence of positive TDP pathology (yes, no) and the ordinalscores for HS were compared across groups using Fisher’s exact test. In the DAT-AD group,

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age was compared between positive and negative TDP groups using the independent samplet test. Age of onset and age of death were compared between TDP pathology groups (positive,negative) using the independent sample t test. Spearman correlation was used to relate TDPpathology scores with HS scores. Logistic regression analysis was used to relate TDP score(negative, positive) to HS scores adjusting for age of death. Statistical significance wasindicated when p<0.05, and no adjustment for multiple testing was made.

ResultsThe modified TDP-43 IHC protocol, the UT Southwestern protocol, and the original TDP-43IHC protocol gave similar results. In the PPA-AD and FTD-AD groups, there were three caseswith TDP-43-positive inclusions of the type associated with FTLD-TDP. Case 26, an FTD-AD case with concomitant FTLD-U (based on the presence of ubiquitin-positive NIIs in thedentate gyrus), clearly also showed moderate numbers of NCIs and DNs and more frequentNIIs with TDP-43 IHC, and also had inclusions in the hippocampus, subiculum, and amygdala(Fig. 1), consistent with amygdala + limbic TDP-43 pathology. This pathology had of coursebeen masked by the AD pathology when ubiquitin IHC was used. An additional FTD-AD case,case 17, was found to have TDP-43-positive inclusions in frontal and temporal cortex,hippocampus, dentate gyrus, entorhinal cortex, and amygdala, consistent with diffuse(amygdala + limbic + neocortical) pathology, and this case was therefore re-classified as AD+ FTLD-TDP (Fig. 2). Case 16, a PPA-AD case with concomitant diffuse Lewy body disease(DLBD), had rare to sparse TDP-43-positive inclusions in the dentate gyrus, entorhinal cortex,and parahippocampal gyrus, and moderate inclusions in the amygdala, consistent withamygdala + limbic stage. Rare amygdala inclusions had the morphology of Lewy bodies orneurofibrillary tangles (Fig. 3). TDP-43 pathology was not present in the other PPA case withDLB (brainstem stage) or the FTD case with DLB limbic stage. Except for these three cases,there was no TDP-43 immunopositivity of NCIs, DNs, or NIIs in any of the other PPA-AD orFTD-AD cases. All three cases had severe neuronal loss and gliosis in the hippocampal CA1region and subiculum consistent with HS, as shown in Fig. 2 for case 17, and none of the otherPPA-AD or FTD-AD cases had HS. In two additional cases, TDP-43 labeled amygdalainclusions with the morphologic appearance of tangles (not shown).

The average TDP score for the combined PPA-AD/FTD-AD group was 0.6 (3/26 had positiveTDP pathology). Taken separately, scores were 0.3 for the PPA group (1/16 or 6% positiveTDP) and 1.1 for the FTD group (2/10 or 20% positive TDP).

In the group of 27 DAT-AD cases, 14 cases (52%) had TDP-43 immunopositive inclusions.In ten cases, these were in dentate gyrus, amygdala, entorhinal cortex, or inferior temporalcortex (amygdala + limbic stage). Four also had rare–moderate inclusions in either frontal orsuperior temporal cortex, consistent with diffuse TDP-43 pathology (inclusions in case 29shown in Fig. 4). Two additional cases had TDP-43 immunopositivity of inclusions with themorphology of tangles.

The average TDP score for the DAT-AD cases was 3.5. In this group, TDP-43 pathology didnot correlate with ApoE status. However, those with TDP-43 immunoreactivity were older atonset (p = 0.003) and death (p = 0.0003). Of the 14 cases with TDP-43 immunopositivity, 9had HS. The average TDP score of these nine cases was 8.5.

Because TDP-43 pathology was found in only three of the 26 PPA-AD and FTD-AD cases(12%), which is much less than the previously reported [1,4,17,18,21,39,41], but was found in52% of the DAT-AD cases, higher than the previously reported, we analyzed our data todetermine why this was so. Paucity of TDP-43 pathology in the PPA-AD and FTD-AD groupsprecluded a correlation between TDP-43 and neuronal loss/gliosis within each of these groups.

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For all three groups combined, the occurrence of positive TDP pathology (yes, no) was highlycorrelated with both hippocampal and subicular neuronal loss/gliosis (Fisher’s exact test). Inthe DAT-AD group, TDP pathology score correlated with both hippocampal (p<0.0001) andsubicular (p<0.0001) neuronal loss and gliosis (Spearman correlation). The occurrence of TDPpathology in the DAT-AD (52%) was significantly greater than in the PPA-AD group (6%,p = 0.003) but not significantly greater than the FTD-AD group (20%, p = 0.14). Hippocampal(p = 0.003) and subicular (p = 0.009) neuronal loss and gliosis were significantly greater in theDAT-AD than in the PPA-AD group. Multivariate logistic regression adjusting for age of deathwas performed in all the cases with TDP-43 pathology, regardless of clinical phenotype. Thisanalysis demonstrated that subicular neuronal loss and gliosis was the only pathologic predictorof TDP-43 immunoreactivity (p = 0.002).

Table 3 shows the semiquantitative estimates for regional TDP-43 pathology and hippocampaland subicular neuronal loss and gliosis for each case. Table 4 summarizes the average TDPscores for each group and the TDP-43 regional sub-types in each group.

DiscussionFrom the neuropathologist’s point of view, AD is defined by the histologic presence of NFTsand neuritic plaques (NPs) in a characteristic density and distribution [2,6,30]. From theclinician’s perspective, DAT, the most typical clinical form of pathologic AD, is characterizedby a progressive amnestic dementia with memory loss the most prominent early sign [27,28].There is general concordance of these clinical and pathologic diagnoses: up to 90% of clinicallydiagnosed late-onset DAT cases have AD pathology at autopsy. This relationship fits the knownearly predilection of AD morphologic pathology, NFTs and eventual neuronal loss, for themedial temporal parts of the brain known to control memory formation.

In addition to amnestic dementia, clinical syndromes of dementia include PPA and FTD. Theseclinical syndromes, especially the PPA variants, can leave memory intact, and would thereforebe expected to have a different neuropathologic basis than typical AD. In fact, most cases ofclinically diagnosed PPA and FTD have neuropathologic changes belonging to the family offrontotemporal lobar degenerations (FTLD). These include FTLD-TDP with or without ALSpathology, FTLD-UPS (most of which are now FTLD-FUS), FTLD-tau [including Pickdisease, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and“unclassifiable tauopathy” pathologic phenotypes], DLDH, and AD pathology [24,27,28,34].FTLD-TDP most often presents clinically with either FTD or PPA, and many patients withFTLD-TDP have clinical and pathologic ALS.

In keeping with the clinical syndrome, the neuronal loss may be most severe in the frontal lobesfor FTD and the left perisylvian cortex for PPA. In our experience, PPA cases with pathologicAD also show asymmetric left perisylvian atrophy but apparently without correspondingconcentration of plaques and tangles. There is one report of the presence of argyrophilic thornyastrocyte clusters (ATAC) in seven of eight cases of PPA-AD and none of six cases of DAT-AD [31]. We previously reported finding multiple clusters of ATAC in only 2 of 11 cases ofPPA-AD [28]. In the current study, we found multiple ATAC in one additional FTD-AD andno additional PPA-AD cases. We also found multiple ATAC in two DAT-AD cases and sparseATAC in two others. Thus far, then, we re-affirm our previous conclusion that these clustersof ATAC may be interesting to follow up on, but they do not appear to provide an answer thatis applicable to all PPA-AD cases [28].

The PPA-AD and FTD-AD cases in the current study had significantly older ages at death andduration of disease than the PPA and FTD cases with non-AD pathology (Table 1), and weconsidered the possibility that their increased age made it more likely for AD pathology to be

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masking an underlying pathologic FTLD. TDP-43 immunohistochemistry allows one, in mostcases, to distinguish between FTLD-TDP and AD, but we found TDP-43 pathologycharacteristic of FTLD-TDP in only three of the 26 cases (12%) of PPA-AD or FTD-AD.

The difference in the prevalence of TDP-43 pathology in our PPA-AD and FTD-AD groups(12%) from what has been reported in AD in general (30%) [1,4,17,18,21,39,41] is striking,and significant (p = 0.046). Although it confirms the findings in our initial study [28], and issimilar to a report by Josephs et al. [20] of PPA with AD pathology, it is very different fromthe 30% reported by Amador-Ortiz et al. in phenotypically typical AD and subsequentlyconfirmed by others [1,4,17,18,21,39,41]. In the group of 26 PPA-AD or FTD-AD cases in thecurrent paper, one could reasonably expect to find TDP-43-positive inclusions in seven or eightcases if the 30% incidence of TDP-43 abnormality is a general feature of AD pathology.Instead, we found “diffuse type TDP-43 immunoreactivity” in only one case, i.e., sufficientcortical and subcortical TDP-43 immunoreactivity for the pathologic diagnosis of FTLD-TDP,and limbic stage TDP-43 pathology in two. One of these, and two additional cases in this group,had TDP-43 labeling of a small subset of medial temporal neurofibrillary tangles or Lewybodies/neurites. The significance of combined immunopositivity for tau or α-synuclein andTDP-43 is not completely clear. However, it raises the possibility that TDP-43 may contributeto pathogenesis in a subset of PPA. There is one report that the presence of TDP-43immunoreactivity in AD modifies the clinicopathologic phenotype in AD [21]. It is unclearwhether this is the case in the current study. TDP-43 immunoreactivity of any type was seenin only two PPA and three FTD cases, making clinicopathologic correlation difficult.Ultimately, though, in the group of PPA and FTD cases with pathologic AD, the incidence ofconcomitant TDP-43 pathology was less than that found in unselected cases of pathologic AD[1].

What is the basis for this difference? One study showed that age of death correlated withTDP-43 pathology in 14 cases of AD, one of two series reported; the other series, containing19 cases, showed no correlation [3]. Another study showed that ages of both onset and deathcorrelated with TDP-43 pathology, but multivariate logistic regression adjusting for age ofdeath showed that TDP-43 pathology correlated only with hippocampal sclerosis [21]. It isinteresting that both studies chose cases with the pathologic diagnosis of AD and neithercompared TDP-43 immunoreactivity by clinical diagnosis. In the DAT-AD group, ages ofonset and death correlated with TDP-43 pathology. When we looked at all three groupstogether, i.e., regardless of the clinical diagnosis, multivariate logistic regression adjusting forage of death revealed that subicular neuronal loss and gliosis was the only pathologic predictorof TDP-43 immunoreactivity (p = 0.003). This is similar to a previous report correlatingTDP-43 pathology with HS [21]. Interestingly, in the current study, hippocampal neuronal lossand gliosis was not a pathologic predictor of TDP-43 immunoreactivity, suggesting that thereis a molecular/pathoetiologic difference between HS with and without subicular neuronal loss.Also interesting is that when all three groups are combined, the percentage of cases withpathologic AD having TDP-43 pathology is 32%, close to the percentage previously reportedin pathologic AD unselected for clinical diagnosis [1,4,17,18,21,39,41].

Similar to our finding that only one of the 16 PPA-AD cases had TDP-43 pathology and HS,another study of five PPA-AD patients showed that none had TDP-43 pathology [20]. HS wasnot specifically mentioned in this paper, but hippocampal neuronal loss and gliosis was less inthis group than in those with “typical AD” [20]. Finally, an analysis of 14 pathologic AD casespresenting clinically with PPA (6 cases), bvFTD (3 cases), and corticobasal syndrome (CBS)(5 cases) demonstrated TDP-43 pathology in only one case, while in the comparison group of14 DAT-AD case 29% had TDP-43 pathology [43]. Interestingly, concurring with the lack ofmemory impairment as a prominent clinical feature, none of the “atypical AD” cases had severeneuronal loss and gliosis in the hippocampus [43]. This differs somewhat from our PPA-AD

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and FTD-AD groups in that the three cases with TDP-43 pathology did have severehippocampal and subicular neuronal loss and gliosis. This may be because of our larger samplesize of 16 PPA and 10 FTD cases, or simply a coincidental fact.

In their paper, Amador-Ortiz and colleagues [1] stated that “most” of their AD cases withTDP-43 immunopositivity had concomitant HS. Because cases of HS alone are known to haveTDP-43 immunopositive inclusions [1,38], the question is whether AD cases with TDP-43immunopositivity have concomitant full-blown FTLD-TDP or simply HS with TDP-43proteinopathy [18]. Significantly, the only PPA-AD or FTD-AD cases that had TDP-43pathology were those cases with concomitant HS. It is most interesting that in the DAT-ADgroup with TDP-43 pathology, the majority of cases had HS, and those with TDP-43 pathologywithout HS had less severe TDP-43 pathology. These cases also had much less neocortical andstriatal pathology than the cases with FTLD-TDP. Do our DAT-AD cases with TDP-43pathology have combined pathologic AD and FTLD-TDP, combined pathologic AD and HSwith TDP-43 proteinopathy, or simply AD with TDP-43 proteinopathy? There is likely notone simple answer to this question, but additional studies investigating these relationships arein progress, which may, in addition, shed light on the question of what the minimal pathologicrequirements are for the diagnosis of FTLD-TDP. In conclusion, this study shows that in thecurrent series of clinical PPA and FTD, FTLD-TDP is rarely combined with pathologic AD,and that medial temporal TDP-43 pathology is more tightly linked to HS than to clinicalphenotype. These findings challenge the current notions about clinicopathologic correlation,especially about the role of multiple pathologies.

Finally, could the cases in the current study have concomitant FTLD-FUS? The discovery thatFUS appears to be the major protein component of the TDP-43-negative inclusions in FTLD-UPS/”atypical FTLD-U” [24,35] exposes a new avenue for us to investigate the basis of theclinical syndrome of PPA or FTD in cases with pathologic AD.

AcknowledgmentsWe are grateful to John Trojanowski and Virginia Lee for their helpful discussions and for sharing their TDP-43immunoprotocol with us. We are most grateful to those patients and family members who so willingly participated inour research programs, without whom our studies are not possible. The study was supported in part by NIH grantsAG13854, AG12300, P30 AG012300, Winspear Family Center for Research on the Neuropathology of AlzheimerDisease, and McCune Foundation.

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14. Geser F, Winton MJ, Kwong LK, et al. Pathological TDP-43 in parkinsonism-dementia complex andamyotrophic lateral sclerosis of Guam. Acta Neuropathol 2008;115:133–145. [PubMed: 17713769]

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16. Hatanpaa K, Bigio E, Cairns NJ, et al. TAR DNA-binding protein 43 immunohistochemistry revealsextensive neuritic pathology in FTLD-U: a Midwest-Southwest Consortium for FTLD Study. JNeuropathol Exp Neurol 2008;67:271–279. [PubMed: 18379440]

17. Higashi S, Iseki E, Yamamoto R, et al. Concurrence of TDP-43, tau and α-synuclein pathology inbrains of Alzheimer’s disease and dementia with Lewy bodies. Brain Res 2007;1184:284–294.[PubMed: 17963732]

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19. Josephs KA, Holton JL, Rossor MN, et al. Frontotemporal lobar degeneration and ubiquitinimmunohistochemistry. Neuropathol Appl Neurobiol 2004;30:369–373. [PubMed: 15305982]

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21. Josephs KA, Whitwell JL, Knopman DS, et al. Abnormal TDP-43 immunoreactivity in AD modifiesclinicopathologic and radiologic phenotype. Neurology 2008;70:1850–1857. [PubMed: 18401022]

22. Lipton AM, White CL III, Bigio EH. FTD-MND predominates in 76 cases of frontotemporaldegeneration. Acta Neuropathol 2004;108:379–385. [PubMed: 15351890]

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25. Mackenzie IR, Shi J, Shaw CL, et al. Dementia lacking distinctive histology (DLDH) revisited. ActaNeuropathol 2006;112:551–559. [PubMed: 16900341]

26. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan E. Clinical diagnosis ofAlzheimer’s disease: report of the NINCDS-ADRDA Work Group* under the auspices ofDepartment of Health and Human Services Task Force on Alzheimer’s Disease. Neurology1984;34:939–944. [PubMed: 6610841]

27. Mesulam M-M. Primary progressive aphasia. Ann Neurol 2001;49:425–432. [PubMed: 11310619]28. Mesulam M, Wicklund A, Johnson N, et al. Alzheimer and frontotemporal pathology in subsets of

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29. Miklossy J, Steele JC, Yu S, et al. Enduring involvement of tau, beta-amyloid, alpha-synuclein,ubiquitin, and TDP-43 pathology in the amyotrophic lateral sclerosis/parkinsonism-dementiacomplex of Guam (ALS/PDC). Acta Neuropathol 2008;116:625–637. [PubMed: 18843496]

30. Mirra SS, Heyman A, McKeel D, et al. The Consortium to Establish a Registry for Alzheimer’sDisease (CERAD), II: standardization of neuropathological assessment of Alzheimer’s disease.Neurology 1991;41:479–486. [PubMed: 2011243]

31. Munoz DG, Woulfe J, Kertesz A. Argyrophilic thorny astrocyte clusters in association withAlzheimer’s disease pathology in possible primary progressive aphasia. Acta Neuropathol2007;114:347–357. [PubMed: 17637999]

32. Nakashima-Yasuda H, Uryu K, Robinson J, et al. Co-morbidity of TDP-43 proteinopathy in Lewybody related diseases. Acta Neuropathol 2007;114:221–229. [PubMed: 17653732]

33. Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration: a consensus on clinicaldiagnostic criteria. Neurology 1998;51:1546–1554. [PubMed: 9855500]

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35. Neumann M, Roeber S, Kretzschmar HA, Rademakers R, Baker M, Mackenzie IRA. Abundant FUS-immunoreactive pathology in neuronal intermediate filament inclusion disease. Acta Neuropathol2009;118:605–616. [PubMed: 19669651]

36. Neumann M, Sampathu DM, Kwong LK, et al. Ubiquitinated TDP-43 in frontotemporal lobardegeneration and amyotrophic lateral sclerosis. Science 2006;314:130–133. [PubMed: 17023659]

37. Olivé M, Janué A, Moreno D, Gámez J, Torrejón-Escribano B, Ferrer I. TAR DNA-binding protein43 accumulation in protein aggregate myopathies. J Neuropathol Exp Neurol 2009;68:262–273.[PubMed: 19225410]

38. Probst A, Taylor KI, Tolnay M. Hippocampal sclerosis dementia: a reappraisal. Acta Neuropathol2007;114:335–345. [PubMed: 17639426]

39. Rohn TT. Caspase-cleaved TAR DNA-binding protein-43 is a major pathological finding inAlzheimer’s disease. Brain Res 2008;1228:189–198. [PubMed: 18634762]

40. Schwab C, Arai T, Hasegawa M, Yu S, McGeer PL. Colocalization of transactivation-responsiveDNA-binding protein 43 and huntingtin in inclusions of Huntington Disease. J Neuropathol ExpNeurol 2008;67:1159–1165. [PubMed: 19018245]

41. Uryu K, Nakashima-Yasuda H, Forman MS, et al. Concomitant TAR-DNA-binding protein 43pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies.J Neuropathol Exp Neurol 2008;67:555–564. [PubMed: 18520774]

42. Weihl CC, Temiz P, Miller SE, et al. TDP-43 accumulation in inclusion body myopathy musclesuggests a common pathogenic mechanism with frontotemporal dementia. J Neurol Neurosurg Psych2008;79:1186–1189.

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Fig. 1.FTD case 26: TDP-43 immunohistochemistry delineates FTLD-TDP pathology. a Dentategyrus with ubiquitin-positive cytoplasmic inclusion that may be neurofibrillary tangle. Originalmagnification 400×. b Dentate gyrus with ubiquitin immunopositive intranuclear inclusion.This indicates combined pathology, but it is impossible to definitively distinguish cytoplasmicAD from FTLDT-DP pathology with ubiquitin. Original magnification 400×. c TDP-43immunopositivity of cytoplasmic inclusion and TDP-43-negative neurofibrillary tangle(arrow) clearly distinguishes AD from FTLDT-DP pathology. Original magnification 600×

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Fig. 2.FTD case 17 has hippocampal sclerosis and TDP-43 immunoreactivity. a Severe neuronal lossand gliosis of both hippocampal CA1 region and subiculum consistent with hippocampalsclerosis. H&E stain, original magnification 20×. b Dentate gyrus with TDP-43-positive NCI(long arrow), NII (arrowhead), and DNs (short arrows). Original magnification 600×. cFrontal cortex with TDP-43-positive NCI (long arrow), NII (arrowhead), and DN (shortarrow). Original magnification 400×

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Fig. 3.PPA case 16: TDP-43 immunopositivity of amygdala inclusions. a The round morphology ofthe inclusion on the right (long arrow) is suggestive of a Lewy body and the more amorphousinclusion (arrowhead) is suggestive of a neurofibrillary tangle, while the neurofibrillary tanglein the center (short arrow) is clearly TDP-43 negative. Original magnification 600×. bConfocal double-label fluorescent immunolabeling using TDP-43, AT8, and α-synuclein. Inthe left column of three figures, TDP-43 (green) and α-synuclein (red) co-localize in roundinclusions (arrows) consistent with Lewy bodies, and an elongated inclusion (arrowhead)consistent with Lewy neurites. There are also clearly inclusions of each type withoutcolocalization. In the middle column, there is no co-localization of TDP-43-positive inclusions(green) and AT8-positive inclusions (red), which include a small dot-like inclusion(arrowhead) and a large intraneuronal neurofibrillary tangle. Likewise, in the right column,there is no co-localization of TDP-43, which labels a nucleus (green, arrowhead) and a largeAT8-positive intraneuronal neurofibrillary tangle (red). Original magnification 600×

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Fig. 4.DAT case 29 with FTLD-TDP type inclusions revealed with TDP-43 IHC. a TDP-43 positivityof several NCIs (long arrows) and one large NII (short arrow) in dentate nucleus. Originalmagnification 600×. b TDP-43 positivity of several NCIs in frontal cortex, some with themorphology of FTLD-TDP NCIs (long arrow) and some with the morphology ofneurofibrillary tangles (short arrow). Original magnification 200×

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Bigio et al.

Tabl

e 1

Clin

ical

info

rmat

ion

of P

PA o

r FTD

with

or w

ithou

t pat

holo

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f AD

Clin

ical

dia

gnos

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thol

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dia

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SD)

Age

of d

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Dur

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ears

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)

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59.8

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10.4

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or F

TDN

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D34

57.6

(10.

4)63

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6.4

(3.6

)


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Bigio et al.

Tabl

e 2

Clin

ical

, pat

holo

gic,

and

gen

etic

info

rmat

ion

of p

atho

logi

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D c

ases

by

clin

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and

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Age

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SD)

Apo

E ε

4 al

lele

pre

senc

e (%

)B

rain

wei

ght (

g) (S

D)

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1610

/660

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11.9

(6.1

)72

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361,

080

(132

)

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107/

358

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8.1

(3.9

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781,

296

(178

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Prob

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2710

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67.9

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78.6

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Bigio et al.

Tabl

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Sem

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estim

ates

of T

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and

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Bigio et al.

Tabl

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TDP43 pathology in primary progressive aphasia and frontotemporal dementia with pathologic Alzheimer...

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Transcript of TDP43 pathology in primary progressive aphasia and frontotemporal dementia with pathologic Alzheimer...